# Inflammatory Caspases in Innate Immunity and Inflammation

> **NIH NIH R37** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $455,000

## Abstract

ABSTRACT
Aspergillus fumigatus (A. fumigatus) is an important human fungal pathogen which is responsible for 
significant morbidity and mortality, particularly among immunocompromised patients. In recent years, we 
have made important progress in understanding the molecular mechanisms that regulate sensing of 
pathogens such as A. fumigatus by pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), 
NOD-like receptors (NLRs), and AIM2-like receptors (ALRs). Certain members of the NLR and ALR family 
assemble a cytoplasmic multi-protein complex termed the ‘inflammasome’, which activates caspase-1 and 
induces maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18 and drives pyroptotic cell 
death. The inflammasome plays critical roles in clearing fungal infections.
My laboratory is a founding member of the inflammasome field and continues to radically advance this 
research area with our pivotal studies, elucidating the mechanisms driving inflammasome activation and 
identifying the importance of these pathways in immune responses. Our strong track record of studies focused 
on inflammasomes and pyroptosis has also allowed us to also make important discoveries about programmed 
cell death pathways. We fundamentally advanced the field of cell death by identifying extensive molecular 
crosstalk among seemingly distinct pathways. For example, we characterized Z-DNA-binding protein 1 (ZBP1) 
as an innate sensor of influenza A virus that triggers the NLRP3 inflammasome and pyroptosis as well as 
apoptosis and necroptosis (PANoptosis). We also identified that PANoptosis is mediated by a complex called 
the PANoptosome, which provides a molecular scaffold that allows interactions and activation of the machinery 
required for the inflammasome/pyroptosis, apoptosis, and necroptosis.
As a result of the significant progress made during the last funding period (which resulted in 129
peer-reviewed papers since the submission of this R37 5 years ago, including publications in Cell, 
Nature, Nature Microbiology, Nature Immunology, and Immunity), we are now in an excellent position
to pursue new directions that will investigate the molecular, biochemical, and cellular mechanism of
inflammasome activation and PANoptosis in response to the global pathogen A. fumigatus. Our 
recent studies demonstrated that the novel A. fumigatus PAMP galactosaminogalactan (GAG) activates the 
NLRP3 inflammasome to drive cell death and in vivo protection against fungal-induced mortality. In addition 
to inflammasome activation, we also recently discovered that A. fumigatus induces PANoptosis and that the 
innate immune sensor ZBP1 is critical for driving inflammatory cell death. However, the molecular 
mechanisms and signaling cascades that regulate and control these pathways, along with the implications of 
PANoptosis in vivo, remain unknown.
In this grant application for extension of our R37, we propose to investigate the signaling pathways ...

## Key facts

- **NIH application ID:** 10829268
- **Project number:** 5R37AI101935-13
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Thirumala-Devi Kanneganti
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $455,000
- **Award type:** 5
- **Project period:** 2012-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829268

## Citation

> US National Institutes of Health, RePORTER application 10829268, Inflammatory Caspases in Innate Immunity and Inflammation (5R37AI101935-13). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10829268. Licensed CC0.

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